The Novel Cognitive Enhancer ST101 Enhances Acetylcholine Release in Mouse Dorsal Hippocampus Through T-type Voltage-Gated Calcium Channel Stimulation
スポンサーリンク
概要
- 論文の詳細を見る
We recently developed a novel cognitive enhancer, ST101 (spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one), that activates T-type voltage-gated calcium channels (VGCCs). Here, we address whether T-type VGCC activation with ST101 mediates its cognitive effects in vivo and the relevance of T-type VGCC activation to acetylcholine (ACh) release in the hippocampus. Acute intraperitoneal administration of ST101 (1 mg/kg, i.p.) improved memory-related behaviors in both olfactory bulbectomized (OBX) and scopolamine-treated mice. Effects of ST101 administration were abolished by both intraperitoneal and intracerebroventricular pre-administration of the T-type VGCC inhibitor mibefradil. Acute administration of ST101 enhanced basal and nicotine-induced ACh release in the dorsal hippocampus in both OBX and sham-treated mice. Enhanced ACh release was abolished by infusion with mibefradil (10 μM) but not with the L-type VGCC inhibitor nifedipine (10 μM). As expected, significantly reduced CaMKIIα, PKCα, and ERK phosphorylation was restored by acute ST101 administration in the OBX mouse hippocampal CA1 region. Enhancement of CaMKIIα and PKCα but not ERK phosphorylation was inhibited by mibefradil (20 mg/kg, i.p.) preadministration. Increased CaMKIIα and PKCα phosphorylation was confirmed by increased phosphorylation of GluR1, synapsin I, and NR1. Taken together, stimulation of T-type VGCCs is critical for the enhanced hippocampal ACh release and improved cognitive function seen following ST101 administration.
著者
-
Han Feng
Institute Of Pharmacology & Toxicology And Biochemical Pharmaceutics College Of Pharmaceutical S
-
Fukunaga Kohji
Department Of Pharmacology Graduate School Of Pharmaceutical Sciences Tohoku University
-
Shioda Norifumi
Department Of Pharmacology Graduate School Of Pharmaceutical Sciences Tohoku University
-
Moriguchi Shigeki
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School:Department of Pharmacology, Tohoku University Graduate School of Pharmaceutical Sciences
-
Moriguchi Shigeki
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan
-
Yamamoto Yui
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan
-
Han Feng
Institute of Pharmacology and Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, China
関連論文
- Advanced Research on Dopamine Signaling to Develop Drugs for the Treatment of Mental Disorders: Proteins Interacting With the Third Cytoplasmic Loop of Dopamine D2 and D3 Receptors
- Transcriptional Regulation of Neuronal Genes and Its Effect on Neural Functions : Expression and Function of Forkhead Transcription Factors in Neurons
- Akt Is a Molecular Target for Signal Transduction Therapy in Brain Ischemic Insult
- β-Amyloid Accumulation in Neurovascular Units Following Brain Embolism
- Functional Proteins Involved in Regulation of Intracellular Ca^ for Drug Development : Role of Calcium/Calmodulin-Dependent Protein Kinases in Ischemic Neuronal Death
- Inhibition of Nitric Oxide Production and Protein Tyrosine Nitration Contribute to Neuroprotection by a Novel Calmodulin Antagonist, DY-9760e, in the Rat Microsphere Embolism(Pharmacology)
- The Post-ischemic Administration of 3-[2-[4-(3-Chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5, 6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole Dihydrochloride 3.5 Hydrate (DY-9760e), a Novel Calmodulin Antagonist, Prevents Delayed Neuronal Death in Gerbil H
- Characterization of αT3-1 Cells Stably Transfected with Luteininzing Hormone β-Subunit Complementary Deoxyribonucleic Acid
- Cytoprotective Effect of 3-[2-[4-(3-Chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole Dihydrochloride 3.5 Hydrate (DY-9760e) Against Ischemia/Reperfusion-Induced Injury in Rat Heart Involves Inhibition of Fodrin
- Spatiotemporal expression of four isoforms of Ca^/calmodulin-dependent protein kinase I in brain and its possible roles in hippocampal dendritic growth